Phase 1 study of WNT pathway Porcupine inhibitor CGX1321 and phase 1b study of CGX1321 + pembrolizumab (pembro) in patients (pts) with advanced gastrointestinal (GI) tumors.

• DOI: 10.1200/jco.2023.41.16_suppl.3514
• Publication Date: 2023-06-04T15:36:10Z
• Authors: Marios Giannakis; Dung T. Le; Michael J. Pishvaian; Benjamin Adam Wei...; Kyriakos P. Papad...; Lin Shen; Jifang Gong; Jian Li; John H Strickler; Aiping Zhou; Wen Zhang; Aparna Raj Parikh; Dustin A. Deming; Gerald Steven Fal...; Jinjin Cai; Laurie Rosenstein; Andrew Dorr; Michael Michael An
• Keywords: Tolerability

3514 Background: Despite the fundamental role of WNT signaling in GI cancers, especially colorectal cancer (CRC), no drug targeting has been successfully developed. CGX1321, a highly-potent and selective inhibitor O-acyltransferase Porcupine, blocks ligand secretion. Preclinical studies show that CGX1321 inhibits growth tumors with RSPO fusions or inactivating RNF43 mutations. Activation associated immune-suppression resistance to immunotherapy. Methods: The first-in-human trials (NCT02675946 U.S., NCT03507998 China) include phase 1 dose escalation (3 – 18 mg, once daily) expansion (18 mg), 1b + pembro combination (Keynote 596). primary objectives were safety, tolerability identification recommended doses schedules for further evaluation. Secondary characterization PK profile PD response anti-tumor activity. was dosed daily, orally, 21 days out 28-day cycles as single-agent, 14 21-day pembro. Results: As January 1, 2023, 77 pts enrolled, including 38 solid escalation, 17 CRC small bowel (SBC) carrying alterations expansion, microsatellite stable (MSS) 5 MSS expansion. Six SBC from single-agent rolled over upon disease progression. Across all cohorts, treatment well tolerated majority AEs being Grade 1/2 not related while > 3 infrequent (~6%). Dysgeusia, common AE observed other inhibitors, mild (mostly 1). Bone resorption, main on-target AE, manageable preventable by prophylactic administration denosumab zoledronic acid. analyses showed adequate exposure significant inhibition measured reduced hair follicle axin2 expression 12 mg dose. Twelve (71%) confirmed tumor genetic had SD median time progression 112 (range: 56 392). Of 6 roll-over cohort, RSPO3 fusion achieved PR during therapy. Conclusions: demonstrated potent pathway side effects. Promising efficacy signals have whose harbor fusion, supporting development monotherapy anti-PD-1/L1 defined patient population is historically known be refractory standard therapies immune checkpoint inhibitors. Clinical trial information: NCT02675946 , .